Lipoxin a4 stimulates calcium-activated chloride currents and increases airway surface liquid height in normal and Cystic Fibrosis airway epithelia

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Abstract

Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl- secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA4 is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA4 are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA4 produced a rapid and transient increase in intracellular Ca2+. We have investigated, the effect of LXA4 on Cl- secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA4 stimulated a rapid intracellular Ca2+ increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA4 stimulated whole-cell Cl- currents which were inhibited by NPPB (calcium-activated Cl- channel inhibitor), BAPTA-AM (chelator of intracellular Ca2+) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA4 increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA4 effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl- secretion. The LXA4 stimulation of intracellular Ca2+, whole-cell Cl- currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA4 in the stimulation of intracellular Ca2+ signalling leading to Ca2+-activated Cl- secretion and enhanced ASL height in non-CF and CF bronchial epithelia. © 2012 Verrière et al.

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Verrière, V., Higgins, G., Al-Alawi, M., Costello, R. W., McNally, P., Chiron, R., … Urbach, V. (2012). Lipoxin a4 stimulates calcium-activated chloride currents and increases airway surface liquid height in normal and Cystic Fibrosis airway epithelia. PLoS ONE, 7(5). https://doi.org/10.1371/journal.pone.0037746

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